N-camphoryl-amino acetamides



United States Patent M 3,130,227 N-CAMPHGRYL-AMENG ACETAP/HDES TorizoTakahashi and I-lajirne Fuiimura, Sakyo-lru,

Kyoto=shi, and Yoshio Hamashima, Atsumi-cho, Atsumi-gun, Aiehi-ken,Japan, assignors to Chugai Seiyaku Kabushiki Kaisha, Tokyo, Japan, acorporation of Japan No Drawing. Filed Aug. 2, 1964 Ser. No. 46,886Claims priority, application Japan Aug. 27, 1959 13 Claims. (Cl.260-557) invention relates to new carnphor derivatives and to processesfor the production of the same. The substances of the present inventionshow analgesic activity and may be used as a medicine.

According to the invention, the camphor derivatives are those in whichalphaamino aliphatic acid amide or its derivatives are introduced in the3-position of the camphor molecule, and they are expressed with thefollowing formula;

wherein R stands for a hydrogen atom, lower alkyl or acetyl radical; R Rand R stand for a hydrogen atom or lower alkyl radical, respectively.

All of these compounds may form a salt such as hydrochloride etc.

The analgesic activity of these compounds may vary more or less,depending on a manner of selection of the radicals, R R R and R but itis always excellent and has low toxicity.

The compounds in the invention are produced by the following processesin which R R R and R stand for the same radicals as those defined aboveunless otherwise stated.

(A) A NR R substituted-(alpha-halogeno aliphatic acid) amide is reactedwith a NR substituted- 3-aminocamphor, and this process is expressed bythe following equation:

wherein X stands for a halogen atom.

(B) An alpha-halogeno aliphatic acid ester is reacted with a NRsubstituted-3-an1-inocamphor to form a N- camphoryl-(3)- z-aminoaliphatic acid ester which is subsequently reacted with a R R-su'ostituted amine, and this process is expressed by the followingequation:

wherein R stands for a lower alkyl radical.

3,130,227 Patented Apr. 21, 1964 The compounds of the general formula:

which are intermediately formed in the above process (B) are newcompounds when the R and R do not stand for hydrogen simultaneously.

The substances of the invention may be prepared as stated above, butthese substances are convertible from one to another as shown below.

(C) The compounds of the invention in which R is hydrogen may beconverted by acetylation into those in which R is an acetyl radical, andthis process is expressed by the following equation:

(D) The compounds of the invention in which R is hydrogen may beconverted by alkylation into those in CHCON which R is an alkyl radical,and this process is expressed by the following equation:

Alkyl R2 R4 These processes are the methods for the production of thecamphor derivatives in accordance with the in-.

reaction may be preferably carried out at -150" C.

using a solvent such as d'nnethylformamide etc. and conveniently in thepresence of a catalytic quantity of an I alkali in the reaction system;and the second step in which the reaction may preferably be carried outat 100-150 C. in a sealed tube using a solvent such as methanol orethanol etc.

The process (C) may be performed by conventional procedure ofacetylation.

'The process (D) may be effected by conventional procedure using asalkylation agent, for example, alkyl halogenide, dialkyl sulfate oralkyl arylsulfonate etc.

I Examples are now given to illustrate but do not restrict the processesfor the production of the camphor derivatives according to theinvention.

EXAMPLE 1 N-Camph0ryl-(3 -Glycine Dimethylamide petroleum ether, thereis obtained as colorless columnar EXAMPLE 2 N-Camphoryl- (3 -GlycineDiethylamide 2 mols. of S-aminocamphor and 1 mol. ofN,-N-diethylchloroacetamide are heated in benzene for 5 hours underreflux. After cooling, the precipitated crystals are filtered and thebenzene is removed from the filtrate. The residue is distilled underreduced pressure, there is obtained N-carnphoryl-(3)-glycinediethylamide as a pale yellow oil; B.P. l64-l65 C./0.02 mm. Hg. Yield79%.

N-camphoryl-(3)-glycine diethylamide hydrochloride are colorless needlesof a melting point of 190 C.

Analysis (as C H O N -HCl): Theoretical-C, 60.64%; H, 9.22%. FoundC,60.88%; H, 9.30%.

EXAMPLE 3 N -M ethyl-N -Cam phoryl- (3 -Glycine Amide 2 mols. of3-methylaminocamphor and 1 mol. of chloroacetamide are heated in benzenein a sealed tube at 100 C. for 7 hours. After cooling, the reactionmixture is Washed with water, dried over anhydrous sodium sulfate anddistilled to remove the benzene. When the residue is recrystallized frombenzene, there is obtained colorless N-methyl-N-camphory1-(3)-glycineamide of a melting point of 139.5 C. Yield 63%.

Analysis (as C H O N Theoretical-C, 65.51%; H, 9.31%. Found-C, 65.75%;H, 9.48%.

EXAMPLE 4 N-Methyl-N-Camphoryl- (3)-Alanine Amide 2 mols. of3-methylaminocamphor and 1 mol. of abromopropionamide are treatedsimilarly to Example 3. On recrystallization from ether, there isobtained N-methyl-N-camphoryl-(3)-alanine amide as colorless plates of amelting point of 109 C. Yield 54%.

Analysis (as C H O N Theoretical-C, 66.63%; H, 9.95%. Found-C, 66.87%;H, 9.65%.

EXAMPLE 5 N-Methyl-N-Camphryl-(3)-Glycine Dimethylamide 2 mols. of3-methylaminocamphor and 1 mol. of N,N dimethylchloroacetamide areheated in benzene for hours under reflux. After cooling, the liquidreaction mixture is washed with water. When the residue is distilledunder reduced pressure, there is obtained N-methyl-2N:camphoryl-(3)-glycine dimethylamide as a pale yellow oil of a boilingpoint of 138140 C./ 0.1 mm. Hg. Yield 68%.

Analysis (as C H O N Theoretical-C, 67.63%; H, 9.84%. FoundC, 67.49%; H,9.92%.

Infra-red absorption shows an absorption of five-membered carbonyl at1740 cm.-

. N-methyl-N-camphoryl-(3)-glycine dimethylarnide hydrochloridecomprises short columnar crystals of a melting point of 174 C.

Analysis (as C H N O -HC1): TheoreticalC, 59.48%; H, 8.99%. FoundC,59.72%; H, 9.17%.

4 EXAMPLE 6 N-Camph0-ryl-(3)-Alanine Dimethylamide 2 mols. of3-aminocamphor and 1 mol. of N,N-dimethyl-ot-chloropropionamide areheated in benzene for 6 hours under reflux. After cooling, theprecipitated crystals are filtered and the benzene removed from thefiltrate by distillation. When the residue is then recrystallized frompetroleum ether, there is obtained as colorless platesN-camphoryl-(3)-alanine dimethylamide of a melting point of 985 C. Yield65%.

Analysis (as C H O N Theoretical C, 67.63%; H, 9.84%. Found-C, 67.85%;H, 10.06%.

EXAMPLE 7 N -M ethy l-N -Camphory l- (3 -A lanine Dimethylamide 2 mols.of 3-methylaminocamphor and 1 mol. of N,N- dimethyl-a-bromopropionamideare heated in benzene in a sealed tube at C. for 20 hours. Aftercooling, the

insoluble matter is filtered and the filtrate has the benzene removed bydistillation. The residue is then distilled under reduced pressure,there is obtained N-methyl-N- camphoryl-(3)-alanine dimethylamide as apale yellow oil of a boiling point of 138-140 C./0.01 mm. Hg. Yield 62%.

N-methyl-N-camphoryl-(3)-alanine dimethylamide hydrochloride comprisescolorless needles of a melting point of 200 C. (decomposition).

Analysis (as C H O N -HCl): TheoreticalC, 60.64%; H, 9.22%. Found-C,60.89%; H, 9.45%.

EXAMPLE 8 N -M ethy l-N -Cam phoryl- (3 -A lam'ne Diethylam'ide 2 mols.of 3-methylaminocamphor and 1 mol. of N,N- diethyl-a-bromopropionamideare heated in toluene for 20 hours under reflux. After cooling, theinsoluble matter is filtered and the toluene is removed from thefiltrate by distillation. When the residue is distilled under reducedpressure, there is obtained N-methyl-N-camphoryl- (3)-alaninediethylamide as a pale yellow oil of a boiling point of 140 C./0.01 mm.Hg. Yield 34%.

Analysis (as C H O N Theoretical-C, 70.09%; H, 10.46%. Found-C, 69.85%;H, 10.68%.

EXAMPLE 9 N-Methyl-N-Camphoryl-(3)-Glycine Ethylester 2 mols. of3-methylaminocamphor and 1 mol. of ethyl chloroacetate are heated indimethylformamide at 120 C. for 8 hours. After cooling, the solvent isdistilled off in vacuo and the residue extracted with ether. After theether is removed, the remainder is distilled under reduced pressure togive N-methy1-N-camphoryl-(3)-glycine ethylester as a pale yellow oil ofa boiling point of 117 C./0.3 mm. Hg. Yield 68%.

N-methyl-N-camphoryl-(3)-glycine ethylester hydrochloride comprisescolorless fine crystals of a melting point of 163-164 C.

Analysis (as C H O N-HCl): Theoretical- C, 59.29%; H, 8.63%; N, 4.61%.FoundC, 59.39%; H, 8.67%; N, 4.89%.

EXAMPLE 10 N -Camphoryl- (3 -A lanine Methylester pale yellow oilof aboiling point of 107109 C./ 0.2 mm. Hg.

Analysis (as C H O N) TheoreticalC, 66.37%; H, 9.15%. Found-C, 66.65%;H, 9.38%.

EXAMPLE 1 1 N -M ethyl-N -Camphryl-(3 -A [an ine M ethylester EXAMPLE 12Theoretical N,

N-Camphoryl-(3 )-Glycine Dimerhyiamide 1 mol. of N-camphoryl-(3)-g1ycineethylester and an excess of 40% dimethylamine in methanol are heated ina sealed tube at 100C. for hours until the yellowish green contentsbecome colorless.

After cooling, the methanol is distilled off. When the residue isrecrystallized from benzene/petroleum ether, there is obtainedN-camphoryl-(3)-glycine dimethylamide as colorless columnar crystals;melting point 126 C. Yield 90% Analysis (as C H O N Theoretical-C,66.63%; H, 9.59%. FoundC, 66.52%;H, 9.62.

The resulting N-camphoryl-(3)-glycine dimethylamide is added tomethanol/hydrochloric acid and the methanol distilled oil to leave asyrup which, on recrystallization from methanol/ ether, givesN-camphoryl-(3)-glycine dimethylamide hydrochloride as flaky crystals;melting point 196 C. (decomposition).

Analysis (as C H O N -HCl-H O): Theoretical-C, 54.80%; H, 8.87%.Found-C, 54.63%; H, 8.96%.

EXAMPLE 13 N-Camplzoryl-(3 -Glycine Diethylamide 1 mol. ofN-camphoryl-(3)-glycine ethylester and 1.2 mols. of die'thylamine areheated in ethanol in a sealed tube at 100 C. for 5 hours. After cooling,the ethanol is distilled off and the residue is subjected todistillation under reduced pressure to give N-camphoryl-(3)-glycinediethylamide as a pale yellow oil of boiling point of 164 165 C./0.02mm. Hg. Yield 87%.

Ncamphoryl-(3)-glycine diethylamide hydrochloride are colorless needlesof a melting point of 190 C.

Analysis (as C H O N -HCl): Theoretical C, 60.64%; H, 9.22%. Found: C,60.51%; H, 9.39%.

EXAMPLE 14 N -M ethyl-N -C am ph0ryl-(3) Glycine Dimethylamide 2 g. ofN-methyl-N-camphoryl-(3)-glycine ethylester and an excess of 40%dimethylamine in methanol are heated in a sealed tube at 100 C. forhours.

After cooling, the reaction mixture is treated similarly to Example 13to give 1.6 g. of N-methyl-N-camphoryl- (3)-glycine dimethylamide as apale yellow oil of a boiling point of 143-145 C./ 0.2 mm. Hg.

N-methyl-N-camphoryl-(3)-glycine dimethylamide hydrochloride as shortcolumnar crystals of a melting point of 174 C.

Analysis (as C H O N -HCl): Theoretical C, 59.48%; H, 8.99%. FoundC,59.59%; H, 9.15%.

6 EXAMPLE 15 N -Camph oryl- (3 -A lanine Dimethylamz'de 2 g. ofN-camphoryl-(3)-alanine methylester and an excess of 40% dimethylaminein methanol are heated in a sealed tube at C. for 10 hours.

After cooling, the methanol is distilled off. When the residue isrecrystallized from petroleum ether, 1.5 g. of N-camphoryl-(3)-alaninedimethylamide is obtained as colorless plates of a melting point of 98C.

Analysis (as C H O N TheoreticalC, 67.63%; H, 9.84%. FoundC, 67.51%; H,9.98%.

7 EXAMPLE 16 N -M ethyl-N -Camphoryl- (3) -A lanz'ne Dimethylamide 2 g.of N-methyl-N-camphoryl-(3)-alan.ine methylester and an excess of 40%dimethylamine in methanol are heated in a sealed tube at 100 C. for 12hours. After cooling, the solvent is distilled ofl? and the residue issubjected to distillation to give 1.4 g. ofN-methyl-N-camphoryl-(3)-alanine dimethylamide as a pale yellow oil of aboiling point of C./0.1 mm. Hg.

N-methyl-N-camphoryl-(3)-alanine dimethylamide hydrochloride arecolorless needles of a melting point of 200 C. (decomposition).

Analysis (as C H O N -HCl): TheoreticalC, 60.64%; H, 9.22%. F0undC,60.73%; H, 9.40%.

EXAMPLE 17 N -A cetyl-N-Camph oryl- (3 -Glycine Dimethylamide 1 g. ofN-camphoryl-(3)-glycine dimethylamide is dissolved in 10 cc. of aceticanhydride and the solution is heated up on a boiling water bath for 3hours. After cooling, the acetic anhydride is distilled oil in vacuo andimpurities are removed from the residue by chromatography with analumina column using chloroform as the solvent. On recrystallizationfrom benzene/ ether, there is obtained N-acetyl-N-camphoryl-(3)-glycinedimethylamide as colorless needles; melting point 131 C. Yield s almostquantitative. 1

Analysis (as C H O N TheoreticalC, 65.28%; H, 8.90. Found C, 65.57%; H,9.08%.

EXAMPLE 18 N -Acetyl-N -Cam phoryl- (3 -Glycine Diezhylamide 1 g. ofN-camphoryl-(3)-glycine diethylamide is dissolved in 10 cc. of aceticanhydride and the solution is warmed over a boiling Water bath for 5hours. After cooling, the acetic anhydride is distilled off. When theresidue is recrystallized from ether/petroleum ether, there is obtainedN-acetyl-N-camphoryl-(3)-glycine diethylamide as colorless needles;melting point 62 C. Yield is quantitative.

Analysis (as C H O N /2H O): Theoretical-C, 65.23%; H, 9.43%. Found-C,65.68%; H, 9.41%.

EXAMPLE l9 N-Acetyl-N-Camphoryl- (3 )Alanine Dimethylamide 1 g. ofN-camphoryl-(3)-alanine dimethylamide is dis solved in 15 cc. of aceticanhydride and the solution heated over a boiling water bath for 6 hours.After cooling, the acetic anhydride is distilled off and the residue isfreed from impurities by chromatography With an alumina column usingchloroform as the solvent. On recrystallization from benzene, there isobtained N-acetyl-N-camphoryl-(3 )-alanine dimethylamide as a colorlesscolumnar crystal; melting point 215 C. Yield is quantitative.

Analysis (as C 7H23O3N Theoretical-C, 66.20; H, 9.15%. FoundC, 66.24; H,9.29%.

EXAMPLE 20 N -M ethyl-N -Cam phoryl- (3 -Glycine Dimethylamide 2 g. ofN-camphoryl-(3)-glycine dimethylamide is dissolved in methanol and thesolution is mixed with 1.5 g. of methyl iodide and (then) with an excessof potassium carbonate. The mixture is subsequently heated in a sealedtube at 100 C. for hours. After cooling, the solvent is distilled offand the residue extracted with ether. When the ether layer is distilledunder reduced pressure, there is obtained 1.8 g. ofN-methyl-N-camphoryl-(3)-glycine dimethylamide as a pale yellow oil of aboiling point of 145 C./ 0.4 mm. Hg.

N-methyl-N-camphoryl-(3)-glycine dimethylamide hydrochloride shows amelting point of 174 C.

EXAMPLE 21 N-Methyl-N-Camphoryl-(3)-Glycine Dimezhylamide 2 g. ofN-camphoryl-(3)-glycine dimethylamide is suspended in 50% methanol and 2g. of dimethyl sulfate are slowly added to the suspension drop-by-dropwith stirring While caustic soda is added so as to keep a slightalkalinity.

After standing for 3 hours with stirring, the reaction mixture isextracted with ether. When the ether layer is distilled under reducedpressure, there is obtained 1.3 g. of N-methyl-N-camphoryl-(3)-glycinedimethylamide as a pale yellow oil of a boiling point of l39l41 C./ 0.1mm. Hg.

EXAMPLE 22 N-Methyl-N-Camphoryl-(S)-Glycine Dimethylamide 8 What weclaim is: 1. A compound of the following Formula 1:

wherein R is a member selected from the group consisting of hydrogen,lower alkyl and acetyl; R R and R are members selected from the groupconsisting of hydrogen and lower alkyl.

. N-camphoryl-(3)-glycine dimethylamide.

N-camphoryl- (3 -glycine diethylamide.

. N-methyl-N-camphoryl-(S)-glycine amide.

. N-methyl-N-camphoryl-(3)-alanine amide.

. N-methyl-N-camphoryl-(3)-glycine dimethylamide.

. N-camphoryl-(3)-alanine dimethylamide.

. N-methyl-N-camphoryl-(3)-alanine dimethylamide.

N-methyl-N-camphoryl-(3)-alanine diethylamide. 10.N-acetyl-N-camphoryl-(3)-glycine dimethylamide. ll.N-acetyl-N-camphoryl-(3)-glycine diethylamide. l2.N-acetyl-N-camphoryl-(3 )-alanine dimethylamide. 13. A pharmaceuticallyacceptable addition salt of a compound of the Formula I as defined inclaim 1.

References Cited in the file of this patent UNITED STATES PATENTS2,192,894 Carswell Mar. 12, 1940 2,692,265 Bruce et al Oct. 19, 19542,746,901 Bruce et a1. May 22, 1956 2,901,507 Speeter et al Aug. 25,1959 2,906,777 Denss et a1 Sept. 29, 1959 FOREIGN PATENTS 663,903 GreatBritain Dec. 27, 1951 206,380 Australia Nov. 17, 1955 OTHER REFERENCESNoller: Chemistry of Organic Compounds, pub. by W. B. Saunders Co.(Phila, Pa), pages 238-240 (1951).

1. A COMPOUND OF THE FOLLOWING FORMULAI:
 2. N-CAMPHORYL-(3)-GLYCINEDIMETHYLAMIDE.